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Novel MST1 inhibitor accelerates murine liver regeneration following partial hepatectomy with improved survival in models of steatohepatitis

ABSTRACT: Disrupted hepatocyte regeneration following surgical resection remains a clinical problem with few therapeutic options. The current treatment paradigm relies on supportive therapy until homeostasis can be achieved. Pharmacologic acceleration of regeneration may provide an alternative therapeutic avenue. Therefore, we aimed to generate a small molecule inhibitor that could accelerate liver regeneration in both normal and diseased murine preclinical models. mCLC846 demonstrated on target inhibition of MST1 and reduced EGFR inhibition which resulted in Yes-associated protein (YAP) activation. Oral delivery of mCLC846 perioperatively resulted in accelerated liver regeneration and improved survival in diet induced NASH models. Transcriptional analysis suggested that mCLC846 enhanced the normal regenerative pathways induced following liver resection. Overall, pharmacological acceleration of liver regeneration with mCLC846 was feasible, had an acceptable therapeutic index, and provided survival benefit in models of diet induced non-alcoholic steatohepatitis.

ORGANISM(S): Mus musculus

PROVIDER: GSE231391 | GEO | 2023/11/01

REPOSITORIES: GEO

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Project description:Surgical resection is the preferred treatment for Hepatocellular carcinoma; however, it induces tumor recurrence. Our objective was to understand the molecular mechanisms linking liver regeneration under chronic-inflammation to tumorigenesis. Mdr2-knockout mice, a model of inflammation-associated cancer, underwent partial-hepatectomy which led to enhanced hepatocarcinogenesis. Yet, liver regeneration in these mice was severely attenuated. We demonstrate the activation of the DNA damage response machinery and altered genomic instability during early liver inflammatory stages resulting in hepatocyte apoptosis and cell-cycle arrest, and suggest their involvement in tumor recurrence subsequent to partial hepatectomy. We propose that under the regenerative proliferative stress induced by liver resection, the genomic unstable hepatocytes generated during chronic-inflammation, escape apoptosis and reenter the cell-cycle, triggering the enhanced tumorigenesis At present, there is a great organ shortage worldwide, thus the main treatment for Hepatocellular carcinoma (HCC) is liver resection. However, liver resection induces recurrence and mortality. In our study, we decipher, for the first time, the contribution of the DNA damage response in HCC development and recurrence, the immediate and long term effect. This is an important finding regarding the association between carcinogenesis and DNA damage response. Additionally, we demonstrate yet another link between inflammation, inducing DNA damage and genome instability, and carcinogenesis that has not been explored in the past. These results may assist in developing treatments that will reduce tumor recurrence and additionally, new prophylactic therapies during early inflammatory stages. Keywords: time course, regeneration RNA was isolated from liver samples of 9-month-old Mdr2-/- and control mice obtained on days 0 (the removed lobe), 2 and 6 following PHx. Samples of d0 were obtained from the same mice that were sacrificed on later days. As we were concerned by the variability in the KO group 6 samples were obtained for d0. All other time points and groups contained 3 samples each.

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Novel MST1 inhibitor accelerates murine liver regeneration following partial hepatectomy with improved survival in models of steatohepatitis

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